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Chimeric antigen receptor specific for interleukin-23 receptor

A chimeric antigen receptor, IL-23 technology, applied in the field of immunotherapy, can solve problems such as inability to obtain

Pending Publication Date: 2021-01-29
САНГАМО ТЕРАПЬЮТИКС ФРАНС
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Additionally, for long-term treatment of autoimmune and / or inflammatory diseases or disorders, induction of tolerance is required, which may not be achievable when targeting cytokines

Method used

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  • Chimeric antigen receptor specific for interleukin-23 receptor
  • Chimeric antigen receptor specific for interleukin-23 receptor
  • Chimeric antigen receptor specific for interleukin-23 receptor

Examples

Experimental program
Comparison scheme
Effect test

no. 1 approach

[0272] According to a first embodiment, the CAR of the invention comprises an extracellular IL-23R binding domain, optionally an extracellular hinge domain, a transmembrane domain and an intracellular signaling domain.

[0273] In one embodiment, the CAR of the present invention comprises an IL-23R binding domain; a CD8 transmembrane domain (preferably SEQ ID NO: 21); and a CD3-ζ first signaling domain (preferably SEQ ID NO: 25 , 26, 61 or 62).

[0274] In one embodiment, the CAR of the present invention comprises an IL-23R binding domain; a CD28 transmembrane domain (preferably SEQ ID NO: 23); and a CD3-ζ first signaling domain (preferably SEQ ID NO: 25 , 26, 61 or 62).

[0275]In another embodiment, the CAR of the present invention comprises an IL-23R binding domain; a hinge domain of CD8 (preferably SEQ ID NO: 13); a transmembrane domain of CD8 (preferably SEQ ID NO: 21); and CD3 - zeta first signaling domain (preferably SEQ ID NO: 25, 26, 61 or 62).

[0276] In one embo...

Embodiment 1

[0597] Example 1: Anti-IL23RCAR Human Treg

[0598] Materials and Methods

[0599] Cells and Reagents

[0600] HEK293T cells (LentiX, Ozyme, France) were cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS).

[0601] Isolation of FoxP3 Treg

[0602] Using EasySepTM human CD4 purchased from StemCell + CD127 低 CD25 + Regulatory T Cell Isolation Kit, freshly isolated CD4 from buffy coat + CD25 + CD127 低 Treg cells. After isolation, purity was assessed by FoxP3 staining. The isolated Treg cells were divided into 5 × 10 per well 5 Cells were seeded in X-VIVO 15 medium (Lonza) in 24-well plates (Costar) and coated with anti-CD3 / anti-CD28 microbeads (Invitrogen, Carlsbad, CA) at a bead to cell ratio of 1:1. activation. Treg cells were activated while receiving rapamycin (100 ng / ml). IL-2 (1000 units / ml, Miltenyi) was added on days 2, 5, 7 and 9.

[0603] CAR construct

[0604]The anti-IL23R CAR construct comprises a human CD8 leader sequence (aa1-22...

Embodiment 2

[0616] Example 2: Anti-IL23R CAR mouse Treg

[0617] Materials and Methods

[0618] Isolation of FoxP3 Treg

[0619] CD4 was freshly isolated from the spleen of C57B16 mice using Life Technologies' Regulatory T Cell Isolation Kit + CD25 + Mouse Treg cells. After isolation, purity was assessed by FoxP3 staining. The isolated Treg cells were divided into 5 × 10 per well 5 10 cells were seeded in RPMI 10% SVF in 24-well plates and activated with anti-CD3 / anti-CD28 coated microbeads (Invitrogen) at a bead to cell ratio of 2:1. Tregs cells received rapamycin (50ng / ml) at the same time as activation and on day 4. Finally, on days 0, 2, 4, IL-2 (1000 units / ml) was added.

[0620] CAR construct

[0621] The anti-mouse IL23R CAR construct used in this experiment (for example, having the nucleic acid sequence of SEQ ID NO:77 and the amino acid sequence of SEQ ID NO:78) contained a human CD8 leader sequence (CD8), a crossover for human / mouse IL23R (αIL23R). Reactive scFv, hinge ...

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Abstract

The present invention relates to a chimeric antigen receptor (CAR) specific for an IL-23 receptor, and to a nucleic acid encoding the same. The present invention further relates to a T cell expressingsaid CAR, and to the use thereof for treating an autoimmune and / or inflammatory disease or disorder.

Description

[0001] field of invention [0002] The present invention relates to the field of immunotherapy. In particular, the present invention relates to chimeric antigen receptors (CARs) specific for the interleukin-23 receptor, to T cells expressing said CARs and to their use in the treatment of autoimmune and / or inflammatory diseases or disorders. [0003] Background of the invention [0004] Interleukin-23 (IL-23) is a member of the IL-12 cytokine family and consists of two subunits, p19 and p40. The IL-23 receptor (IL-23R) consists of the IL-23Rα subunit complexed with the IL-12Rβ1 subunit, which is a common subunit of the IL-12 receptor and interacts with tyrosine kinase 2 (Tyk2) . IL-23R constitutively associates with Janus kinase 2 (JAK2) and associates with STAT3 and STAT4 upon activation by IL-23. [0005] IL-23R is mainly expressed on immune cells, especially T cells (such as Th17 and γδ T cells), macrophages, dendritic cells and NK cells (Duvallet et al., 2011). It has re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K14/705A61P37/02
CPCC07K16/2866C07K2317/622C07K2319/03C07K2319/33A61K2039/505A61P37/02C07K14/70578C07K14/7051C07K2319/02A61K39/4621A61K39/46433C12N5/0636C12N5/0637A61K39/4611A61K39/464419A61K2239/31A61K2239/38A61K39/4631C07K14/70517C12N15/85C12N2510/00A61K35/17A61P17/00A61P29/00
Inventor T·亚伯J·格特纳-达登内F·迈耶
Owner САНГАМО ТЕРАПЬЮТИКС ФРАНС